Carbamazepine medicament with retarded active substance release

ABSTRACT

An oral administration carbamazepine medicament with a retarded active substance release is disclosed. An aqueous plasticised polymer dispersion is applied on carbamazepine crystals without causing formation of carbamazepine dihydrate. The carbamazepine crystals with their aqueous coating may be mixed with appropriate auxiliarly substances, shaped into divisible tablets or filled into capsules.

This application is based on German Patent Application DE 4423078.8filed Jul. 1, 1994 and PCT/DE95/00805, filed Jun. 22, 1995, the contentsof which are incorporated hereinto by reference.

BACKGROUND OF THE INVENTION

The invention is relative to an orally applicable carbamazepinemedicament with retarded active substance release. Carbamazepine, a 5H-dibenz(b,f)azepine-5-carboxamide, is used in particular as anantiepileptic. Commercial forms of administration are tablets with 200mg active substance, delayed-action tablets with 200 to 600 mg activesubstance and syrups.

It is known that carbamazepine very rapidly forms a dihydrate uponcontact with water. This dihydrate is present in a crystalline form asneedles which can grow up to a particle size of 500 μm. This has anegative effect on the further processing, especially when developingretarding coatings. The known methods of production therefore do not useaqueous media and prefer to use organic solvents.

The retarding of an active substance can take place in various ways. DEpatent 23 77 520 describes a formulation for carbamazepine in which theactive substance is mixed with customary inactive tableting ingredientsand pressed to a core or filled into capsules. The core or the capsuleis coated with a methacrylic acid-methacrylic acid methylester mixturedissolved in isopropanol which mixture contains acetyltributylcitrate assoftener. In this manner the forming of dihydrate by carbamazepine isprevented by the use of an organic solvent.

DE patents 38 68 077 and 37 25 824 claim a carbamazepine inactiveingredient composition containing a protective colloid which inhibitsthe crystalline growth of carbamazepine in the presence of water. Thecarbamazepine-containing core is coated in them with an organic solventof cellulose acetate. A passage in the form of a perforation is placedin the film in a suitable manner.

The methods of producing these formulations have the disadvantage thatthe work must be carried out with organic solvents, which impacts theenvironment and signifies great effort and expense.

Furthermore, these medicaments produced as described above (tablets andcapsules) are not divisible, since the casing is damaged in a divisionand the retarding action is lost therewith. Thus, the dosingpossibilities are limited.

In addition, preparations (tablets) are known which do not lose theirretarding action in a division or a disintegration into individualparticles in liquids outside of or within the gastrointestinal tract.Pharm. Ind. 55, No. 10 (1993) pp. 940-947 describes compact oralpreparations in which individual particles are coated with aqueousdispersions of copolymers of methacrylic acid and methylmethacrylic acidesters and pressed to tablets. The addition of 25-50% inactiveingredients brings about a more rapid decomposition of the tablets. Theaddition of a softener makes it possible to considerably increase theelongation at break of the coating and assures the mechanical stability.The coating of paracetamol-, potassium chloride- and acetylsalicylicacid active substance crystals, theophylline granulate and indomedacineand theophylline pellets are cited in this connection.

The present invention has the problem of making available acarbamazepine medicament in which, in spite of the use of water assolvent or dispersing agent, the crystal growth associated with theformation of dihydrate by the carbamazepine is prevented and the releaseof the carbamazepine is sufficiently retarded.

SUMMARY OF THE INVENTION

The invention solves the problem in that film formers are applied incombination with a softener as aqueous solution and/or dispersion ontocarbamazepine. The coated carbamazepine can optionally be mixed withfurther inactive ingredients and pressed to tablets or filled intocapsules.

DETAILED DESCRIPTION OF THE INVENTION

Polymethacrylate dispersions are used as film formers for the retardingof carbamazepine. The following are preferred:

A mixture of polyethylacrylate and polymethylmethacrylate in a ratio of2:1 (Eudragit® NE 30 D),

A mixture of polyethylacrylate, polymethylmethacrylate andpolytrimethylammonioethylmethacrylate chloride in a mixture of 1:2:0.1(Eudragit® RS 30 D) or

The previously cited mixture in a ratio of 1:2:0.2 (Eudragit® RL 30 D).

Potential water-soluble softeners are e.g. glycerol triacetate ortriethylcitrate. They are used in a ratio of dry lake substance tosoftener such as 1:0.05 to 1:0.25, preferably 1:0.15 to 1:0.22.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates graphically the release curves for different ratiosof carbamazepine to film former.

FIG. 2 illustrates graphically the retardation rate of the dissolutionrate for carbamazepine and coated carbamazepine according to theinvention.

The ratio of film former to carbamazepine is a function of the retardingeffect to be achieved and is 1:0.03 to 1:0.5. In particular, a ratio ofcarbamazepine to film former of 1:0.05 to 1:0.1 is used, but preferably1:0.05 to 1:0.08.

The release curves for such different ratios of carbamazepine to filmformer are shown in FIG. 1. The Dissolutions test of USP XXII forcarbamazepine was used as method (medium: Water with 1% sodiumdodecylsylfate additive).

Surprisingly, the composition of the carbamazepine medicament inaccordance with the invention was able to prevent the dihydrateformation which occurs spontaneously, as is known, when carbamazepinemakes contact with water and with is associated with a needle-likegrowth of crystals and thus to prevent poor processability.

The film former combined with a softener is advantageously sprayed on asaqueous solution and/or dispersion in a fluid-bed granulator. Inaddition, in order to prevent the adhering of the coated particlesseparating agents can be added to the dispersion and/or sprayed onsubsequently in the fluid bed as separate suspension. For example,talcum is applied in a concentration ratio of dry lake substance toseparating agent such as 1:0.4 to 1:1, preferably 1:0.45 to 1:0.55.

Further galenic inactive ingredients can be mixed in with the coatedcarbamazepine crystals in a known manner. the mixtures produced in thismanner or even the coated crystals can then be filled into hard gelatinecapsules or pressed to divisible tablets. The mechanical stressing ofthe individual particles associated with the cited further processing ofthe coated carbamazepine, especially in tabletting, does not damage thefilm coating.

The final medicament displays the same retardation of the dissolutionrate, tested according to the method of USP XXII for carbamazepine, asthe coated carbamazepine (FIG. 2).

The method of the invention is explained in detail using the exemplaryembodiments:

EXAMPLE 1

A suspension is produced from 2.23 kg Eudragit RS 30 D, 135 g glyceroltriacetate dissolved in 2.35 l water and 325 g talcum suspended in 1 lwater. The suspension is sprayed on 10 kg carbamazepine in a WSG 15fluid-bed granulator (Glatt company). Then, a suspension of 625 g talcumin 2 l water is sprayed on. The granulate obtained in this manner ismixed with 914 g microcrystalline cellulose, 653 g insoluble polyvidone,70 g highly disperse silicon dioxide and 35 g magnesium stearate. Themixture is pressed to tablets with an active-substance content of 200,400 or 600 mg carbamazepine or the corresponding amount of granulate isfilled into capsules of size 1.

EXAMPLE 2

A suspension is produced from 340 g Eudragit RS 30 D, 20.4 gtriethylcitrate dissolved in 0.3 l water and 40 g talcum suspended in0.1 water. The suspension is sprayed on 1 kg carbamazepine in a GPCG 1fluid-bed granulator (Glatt company) at a product temperature of 27°-30°C. The granulate obtained in this manner is mixed with 65 gmicrocrystalline cellulose, 65 g insoluble polyvidone, 7 g highlydisperse silicon dioxide and 3.5 g magnesium stearate. The mixture ispressed to tablets with an active-substance content of 200, 400 or 600mg carbamazepine or the corresponding amount of granulate is filled intocapsules of size 1.

EXAMPLE 3

A suspension is produced from 29 g Eudragit NE 30 D, 1.3 g glyceroltriacetate dissolved in 0.03 l water and 9 g talcum suspended in 0.03water. The suspension is sprayed on 250 g carbamazepine in a Glatt UNIfluid-bed granulator at a product temperature of 27°-30° C. Thegranulate obtained in this manner is mixed with 16 g microcrystallinecellulose, 16 g insoluble polyvidone, 2 g highly disperse silicondioxide and 1 g magnesium stearate. The mixture is pressed to tabletswith an active-substance content of 200, 400 or 600 mg carbamazepine orthe corresponding amount of granulate is filled into capsules of size 1.

We claim:
 1. A method of producing a carbamazepine medicament withretarded active substance release comprising spraying film formers incombination with softener as an aqueous solution or an aqueousdispersion onto carbamazepine in a fluid-bed granulator to form a coatedcarbamazepine and filling the coated carbamazepine without furtherinactive ingredients into capsules.